By Dr. Geoffrey Modest
A recent trial looked at the effect of on-demand short courses of TDF/FTC (tenofovir/emtricitabine) in preventing HIV transmission in men at high risk (see N Engl J Med 2015;373:2237-46). There was a prior blog on pre-exposure prophylaxis from the PROUD trial, with continuous use of TDF/FTC, and included a brief report on the IPERGAY trial prior to publication — see http://blogs.bmj.com/bmjebmspotlight/2015/10/05/primary-care-corner-with-geoffrey-modest-md-hiv-pre-exposure-prophylaxis/ . The full report on IPERGAY was just released, and I think it is so important that it is worth reviewing in some detail.
- 400 men without HIV infection but who had a history of at least 2 encounters of unprotected anal sex with men within the past 6 months. Those with hepatitis B or C were excluded, as well as those with eGFR <60ml/min, ALT > 2.5 times normal, and glycosuria or proteinuria >1+ on urine dipstick.
- Intervention: those randomized to active drug took TDF/FTC (300mg/200mg), 2 pills 2-24 hours prior to sex, then a third pill 24 hours later and a fourth 24 hours after the third, vs taking placebo. In cases of multiple sexual exposures, patients were instructed to take 1 pill/day until the last exposure, then 2 post-exposure pills. If there were exposure within 1 week of the last 4 pill dosing, then the patient took only 1 initial pill prior to the next exposure. All participants received risk-reduction counseling from a peer community member and condoms
- Demographics: mean age 35, 90% white, 73% not in monogamous relationship/8% in a relationship with HIV-1 positive partner, 72% with postsecondary education, 45% used recreational drugs and 23% >5 alcoholic drinks/d. 5 enrollment sites in France and one in Montreal. followed median of 9.3 months
- 56 of the patients received post-exposure prophylaxis (31 in TDF/FTC group, 25 in placebo)
- Median of 15 pills taken/month in each group
- Adherence — of 113 patients tested: 86% had TDF and 82% FTC in their blood, consistent with taking the med within the past week. TDF and FTC were found in 8 people on placebo, 3 of whom were on postexposure prophylaxis. Overall adherence: 28% did not take TDF/FTC or placebo; 29% took suboptimal doses, and 43% took the assigned drug correctly
- No difference in sexual practices from before to during the study, though the placebo group did have a significant decrease in the number of sexual partners
- 40% had a new sexually-transmitted infection during the study (20% got chlamydia, 22% gonorrhea, 10% syphilis, 1% hep C), confirming continued high-risk sexual practices
- 16 HIV infections happened after enrollment: 2 in the TDF/FTC group (0.91/100 person-yrs) and 14 in the placebo group (6.60/100 person-yrs), with relative risk reduction of 86% (36-97%, p=0.002)
- The 2 HIV infections in the TDF/FTC group were in men nonadherent to pre-exposure prophylaxis (pill counts showed no meds taken and no meds were detected in the serum at the time of HIV diagnosis)
- Adverse events: no significant difference in frequency of grade 3 or 4 adverse events (which were pretty much nonexistent), though there were more GI adverse events, esp nausea in 8% of those on TDF/FTC and 1% placebo and abdominal pain in 7% vs 1%. There was a transient decrease in eGFR to <60 in 2 people on TDF/FTC
So, remarkably similar results to the PROUD trial with daily TDF/FTC. A few points:
- These results are also similar to the iPrex trial (see Lancet Infect Dis 2014; 14: 820), which in their open-label extension found that those who had intracellular TDF levels consistent with taking at least 4 tablets/week had no incident HIV infections, very similar to the number of pills in IPERGAY (median of 15 pills/month), and adding to the validity of the IPERGAY results.
- IPERGAY was a really short-term study, which not only may overestimate the effectiveness in clinical practice (over time, patients may become weary of taking meds each time they have sex) and underestimate adverse effects (too short a med exposure to see chronic renal disease, for example). Also raises the question of whether we need to monitor for adverse effects with intermittent dosing of TDF and how to do so (e.g., see blog http://blogs.bmj.com/bmjebmspotlight/2015/07/23/primary-care-corner-with-geoffrey-modest-md-tenofovir-nephrotoxicity/ on how to monitor TDF renal toxicity in those on daily TDF)
- But it seems from all of the pre-exposure prophylaxis studies, that TDF/FTC works, and if you look at the subset of patients who actually take the drug, it essentially always works.
- Overall, in these studies, there were not a lot of HIV infections, but it would be really interesting to know if this even regimen works in patients who have TDF or FTC resistant viruses, given that in some areas resistance is pretty common (i.e., useful to have a trial in a community of people with frequent HIV resistance mutations). It may well be that people need only a single active agent, so that the combo TDF/FTC would still work for many people in communities with resistant HIV infection. For example, in a South African study in women using tenofovir vaginal gel, there was a 54% lower rate of HIV acquisition in those who were high adherers to the treatment (see Science 2010;329(5996):1168) – i.e. using TDF only
- It would be really useful to know if starting the TDF/FTC right after unprotected sex worked, since my guess is that adherence would be better than anticipating sex and remembering to take the pills at least 2 hours before.
- Also, these studies with TDF/FTC were done in predominantly white, educated MSM communities, so would be useful to see how this on-demand approach works in poorer communities, in communities where the predominant spread is heterosexual or through drugs, and in minority communities.
I will add a comment from Jon Pincus about a blog sent out on the new release of meds with TAF (tenofovir alafenamide, which has less renal and bone toxicity, and is as effective as TDF) — see http://blogs.bmj.com/bmjebmspotlight/2015/11/17/primary-care-corner-with-geoffrey-modest-md-new-hiv-1-drug-approved-by-fda/
So I know you don’t buy into big pharma conspiracies but……..
Odd that Gilead is releasing the combo pill long before the individual TAF or TAF/FTC pill. TAF I believe is due for an FDA vote in April 2016.
Coincidence that TDF patent is set to expire I believe in 2017 and that Gilead’s blockbuster single pill HIV drug, Atripla, was just bumped off its pedestal in the last Guidelines and is losing market share to triumeq [that is: abacavir/dolutegravir/lamivudine; and for the last guidelines, see http://blogs.bmj.com/bmjebmspotlight/2015/04/17/primary-care-corner-with-geoffrey-modest-md-updated-hiv-guidelines-2015/ for details]
All just coincidence I’m sure……